Over the years we have been characterizing mice with different Akt isoforms deficiencies for survival, lifespan, and susceptibility to cancer. The current renewal application is focused on new and unexpected observations made during the last funding period. These observations are: (i) Systemic whole body deletion of Akt1 in adult mice inhibits tumor progression in a mouse cancer model that is not driven by Akt activation. (ii) The deletion of either Akt1 or Akt2 does not inhibit liver carcinogenesis, and Akt2 deletion increases lung metastasis induced by liver carcinogenesis. (iii) The deletion of both Akt1 and Akt2 in the liver induces spontaneous hepatocellular carcinoma (HCC). (iv) Germ line deletion of Akt1 and Akt3 causes embryonic lethality, but the systemic deletion of Akt1 and Akt3 in adult mice is well tolerated. (v) The deletion of Akt1 increases the lifespan of mice. (iv) The systemic deletion of Akt1 and Akt2 in adult mice induces rapid mortality. These findings suggest that drugs, which target predominately Akt1 and not Akt2 could be effective and well tolerated in cancer therapy. By contrast, drugs that effectively inhibit both Akt1 and Akt2 could be deleterious and pro-liver carcinogenesis. Since Akt activation is perhaps the most frequently event occurring in human cancers, and targeting Akt activation for cancer therapy is in progress, our studies should have a profound impact on cancer therapy. The overall goal of this project is to determine the physiological consequences of Akt deletion in the mouse and their underlying mechanisms with implications to cancer therapy.